tbuckley/cabot-search huggingface dataset:
Abstract 5027: PTMcosmos: A web portal of post-translational modifications and proteogenomic resources in cancer
Authors: Liang-Bo Wang, Akshay Govindan, Song Cao, Li Ding
Journal: Cancer Research (2022)

Abstract PTMcosmos is a comprehensive database with an interactive web portal designed to catalog and visualize post-translational modifications (PTMs) in humans. It contains 469,183 experimentally-validated PTM sites and their supporting evidence from UniProt Knowledge Base, PhosphoSitePlus, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). PTMcosmos summarizes the entire spectrum of CPTAC proteomics data on human cancer patients, including protein and PTM peptide abundance data from 10 different cancer types. Additionally, PTMcosmos contains cancer somatic mutations from The Cancer Genome Atlas (TCGA), thus allowing for the collective integration and analysis of different data types. In PTMcosmos, we have built an ensemble of interactive visualization tools that allow researchers to investigate altered PTM functions due to genetic alterations in close proximity. The database is live at https://ptmcosmos.wustl.edu. We used PTMcosmos to investigate PTM regulation across cancer types. First, we examined the differential abundance of the PTM sites of cancer driver genes, focusing primarily on phosphorylation of the tumor suppressor retinoblastoma protein (encoded by RB1) and acetylation of the histone acetyltransferase E1A Binding Protein P300 (EP300) across cancer types. We analyzed the association between these PTM events and downstream targets, as well as with tumor subtypes, significantly mutated gene (SMG) mutation status, and clinical features. Second, we investigated the association of the protein abundance of cancer driver genes with ubiquitylsites in lung squamous cell carcinoma (LSCC) to nominate potentially novel modes of regulation of these proteins’ activities. We further analyzed the tumor subtype specificity and tumor-normal abundance changes of these ubiquitylsites and their corresponding substrate proteins, identifying several EGFR ubiquitylsites which may regulate EGFR abundance in LSCC. Finally, we identified the linear and spatial clustering of mutations and PTM sites, identifying multiple mutation-PTM clusters in cancer related genes, including TP53, PIK3CA, CTNNB1, EGFR, and IDH1. We envision that PTMcosmos will serve both the CPTAC consortium and the wider research community to better understand the role of PTMs in cancer. Citation Format: Liang-Bo Wang, Akshay Govindan, Song Cao, Li Ding. PTMcosmos: A web portal of post-translational modifications and proteogenomic resources in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5027.
A core outcome set for post-COVID-19 condition in adults for use in clinical practice and research: an international Delphi consensus study
Authors: Daniel Munblit, Timothy Nicholson, Athena Akrami, Christian Apfelbacher, Jessica Chen, Wouter De Groote, Janet V Diaz, Sarah L Gorst, Nicola Harman, Alisa Kokorina, Piero Olliaro, Callum Parr, Jacobus Preller, Nicoline Schiess, Jochen Schmitt, Nina Seylanova, Frances Simpson, Allison Tong, Dale M Needham, Paula R Williamson, Alla Guekht, Malcolm “Calum” G. Semple, John O. Warner, Louise Sigfrid, Janet T. Scott, Audrey DunnGalvin, Jon Genuneit, Danilo Buonsenso, Manoj Sivan, Bob Siegerink, Frederikus A. Klok, Sergey Avdeev, Charitini Stavropoulou, Melina Michelen, Olalekan Lee Aiyegbusi, Melanie Calvert, Sarah E. Hughes, Shamil Haroon, Laura Fregonese, Gail Carson, Samuel Knauss, Margaret O'Hara, John Marshall, Margaret Herridge, Srinivas Murthy, Theo Vos, Sarah Wulf Hanson, Ann Parker, Kelly K. O'Brien, Andrea Lerner, Jennifer R. Chevinsky, Elizabeth R. Unger, Robert W. Eisinger, Catherine L. Hough, Sharon Saydah, Jennifer A. Frontera, Regis Goulart Rosa, Bin Cao, Shinjini Bhatnagar, Ramachandran Thiruvengadam, Archana Seahwag, Anouar Bouraoui, Maria Van Kerkhove, Tarun Dua, Pryanka Relan, Juan Soriano Ortiz
Journal: The Lancet Respiratory Medicine (2022)
Abstract 498: TARE and PVE as pre-operative strategies in highly selected patients with primary and metastatic hepatic malignancies
Authors: Julia Pedo Freitas, Pradeep Podila, Daniel K. Powell, Wes Angel, Jeremiah L. Deneve, Paxton V. Dickson, Evan S. Glazer
Journal: Cancer Research (2022)

Abstract Background: The treatment of malignancies confined to the liver (hepatocellular carcinoma [HCC], intrahepatic cholangiocarcinoma [ICC], metastatic neuroendocrine tumors [NET] and colorectal hepatic metastases [CRHM]) is challenging. Liver resection leading to post-operative liver failure is a devastating complication that can be mitigated by pre-resection embolization techniques to increase the future liver remnant, such as portal vein embolization (PVE) and transarterial radioembolization (TARE). The purpose of this study was to understand the natural history of this treatment algorithm in disparate patient populations. Methods: This was a retrospective case-control study from 2008 to 2018. The population consisted of non-transplant eligible patients that had various malignancies without extra-hepatic disease who underwent TARE, PVE, or resection at our institution; they were propensity matched based on co-morbidities, etiology of liver disease, Child-Pugh Score, and ECOG performance status. Statistical analyses were performed with chi-square. Results: We identified 196 patients with an average age of 57.8±12.6 years and 119 patients were male (60.7%). There were 137 Caucasian patients (CC, 70%) and 59 African American patients (AA, 30%). The tumor histologies were 61 HCC, 31 ICC, 65 CRHM, 12 NET, and 28 other. 148 of these patients underwent liver resection. HCC patients were more likely to undergo TARE (36.4%) compared to ICC (20%), CRHM (23.6%), or NET (9.1%, P= 0.043). While AA patients were more likely to undergo any embolization procedure compared to CC patients (47% vs 31%, P=0.03), they were less likely to undergo PVE (P=0.018). 126 patients (64%) did not undergo any pre-resection embolization procedures. Of patients requiring pre-resection embolization, CRHM patients were more likely to undergo PVE (80%) than other patients (P=0.029). TARE was a bridge to resection for 9 patients. Conclusions: AA patients underwent more embolization procedures compared to CC patients. It is not clear whether this was because that population required more interventions to optimize FLR or had limited access to care. Citation Format: Julia Pedo Freitas, Pradeep Podila, Daniel K. Powell, Wes Angel, Jeremiah L. Deneve, Paxton V. Dickson, Evan S. Glazer. TARE and PVE as pre-operative strategies in highly selected patients with primary and metastatic hepatic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 498.
Abstract 1767: A next generation site-specific ADC targeting breast and gastric cancer
Authors: James Sebastian Italia, Nikos Biris, Zhi Li, Myer Hussain, John Boyce, Audrey Warner
Journal: Cancer Research (2022)

Abstract Antibody drug conjugates are entering a renaissance period as a promising treatment option for a variety of cancers. Despite some success in the past few decades, developing effective ADCs remains a challenge due to extensive inefficiencies of industry standard conjugation technologies. Industry available methods can be limited by lack of site-specificity, inflexibility on the site of conjugation, and poor overall biophysical characteristics which can alter the efficacy, safety, and bioavailability of these therapeutics. BrickBio’s unique bioconjugation methodology enables precise (site-specific), flexible (offering numerous options for conjugation site and chemistry), efficient, and scalable generation of antibody-drug conjugates which overcome these limitations and achieve the full potential of this highly promising class of therapeutics. In this work, we incorporate an azide-containing UAAs (unnatural amino acid) into full-length antibodies targeting receptors overexpressed in breast and gastric cancer. Specifically, we have engineered variants of IgG1 antibodies to contain the aforementioned UAA, enabling site-specific attachment of cytotoxic payloads, such as auristatins, via click chemistry to generate ADCs with homogeneous DARs and at different conjugation sites. The resulting BrickADCs exhibit high therapeutic efficacy against receptor-positive cell lines, particularly lines expressing low levels of HER2, in vitro as well as in mouse xenograft models. Not only are the BrickADCs 100x more potent in demonstrated cell lines, but current research indicate that they have an improved safety profile over T-DM1. In other efforts, the BrickADC platform is leveraging a proprietary Modular Multisite Platform (MMP) to address the unmet need of eventual ADC resistance by conjugating multiple distinct payloads in a homogenous fashion. Continued preclinical work is underway for these pipeline candidates as well as investigation into other target areas. Citation Format: James Sebastian Italia, Nikos Biris, Zhi Li, Myer Hussain, John Boyce, Audrey Warner. A next generation site-specific ADC targeting breast and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1767.
Abstract 6352: Ascites derived exosomes promote progression of advanced gastric cancers
Authors: Sujin Hyung, Jihoon Ko, In-kyung Lee, Noo Li Jeon, Jeeyun Lee
Journal: Cancer Research (2022)

Abstract Gastric cancer (GC) with peritoneal metastasis accompanied by a sequential buildup of malignant ascites currently has no curative therapy; accordingly, developing novel biomarkers is critical for reducing the severity of this disease. Recently, the significance of exosomes as a biomarker has gradually increased; exosomes act as a critical mediator of cell-cell intracellular communication in cancer progression. In this study, we characterized exosomes derived from ascites (ExoAscites) of four patients with GC; the high concentration of ExoAscites was observed with the morphology of round-cup shape. Our results showed that ExoAscites were actively endocytosed into cancer spheroid with time. The tropism of ExoAscites showed a predominance to GC rather than stromal cells.Furthermore, their importance on cancer invasiveness and angiogenesis are verified in the 3D microfluidic cancer spheroid model. Interestingly, tumor progression was gradually promoted by treatment with increasing ExoAscites concentrations. Collectively, these results support the view that exosomes from ascites fluids act as mediators of the tumor microenvironment, thus providing conditions favorable for future tumor progression. Citation Format: Sujin Hyung, Jihoon Ko, In-kyung Lee, Noo Li Jeon, Jeeyun Lee. Ascites derived exosomes promote progression of advanced gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6352.
Abstract 820: Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression
Authors: Adam T. Nelczyk, Hashni E. Vidana Gamage, Liqian Ma, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Anasuya Das Gupta, Natalia Krawczynska, Sisi He, Michael J. Spinella, Erik R. Nelson
Journal: Cancer Research (2022)

Abstract The primary purpose of our work was to characterize the effects of the nuclear receptor TLX (NR2E1) in triple-negative breast cancer (TNBC) in order to evaluate its potential therapeutic value in a subtype of breast cancer that has proven particularly challenging to treat, primarily due to the lack of targeted modes of intervention. Unfortunately, breast cancer continues to be the second deadliest form of cancer among women in the United States. Considering the substantial public health implications, development of new therapeutic strategies for highly aggressive breast cancer subtypes, such as TNBC, is imperative. While the function of nuclear receptors such as the estrogen and androgen receptors has been extensively characterized in cancers of the breast and prostate respectively, due in part to their amenable nature to ligand modulation, it is likely that other nuclear receptors may represent therapeutic targets for these malignancies. Indeed, probing of available clinical datasets demonstrated that nuclear receptor TLX is most highly expressed in basal and estrogen receptor (ER)-negative breast cancer patients, and that ER-negative patients with higher TLX expression had increased relapse-free and overall survival. Therefore, we hypothesized that TLX could influence the pathophysiology of TNBC. Utilizing a stable overexpression model in the TNBC cell lines, MDA-MB-231 and MDA-MB-468, we have shown that TLX can inhibit critical oncogenic properties in the in vitro setting, including proliferation, migration and invasion. Furthermore, xenograft and lung colonization studies demonstrated that TLX continued to exert anti-oncogenic effects in the in vivo environment. In agreement with these results, transcriptomic analysis of TLX-overexpressing cells and xenograft tumors showed that TLX can regulate genes and pathways that are known to play crucial roles in the growth and metastatic dissemination of cancer. As previously published works have identified several putative TLX ligands, our findings demonstrating that TLX functions as an anti-cancer factor in TNBC provides a strong rationale for future research aimed at therapeutically targeting this nuclear receptor. Citation Format: Adam T. Nelczyk, Hashni E. Vidana Gamage, Liqian Ma, Michael T. McHenry, Madeline A. Henn, Mohammed Kadiri, Yu Wang, Anasuya Das Gupta, Natalia Krawczynska, Sisi He, Michael J. Spinella, Erik R. Nelson. Nuclear receptor TLX inhibits cancer cell intrinsic properties required for triple-negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 820.
Abstract 242: TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells
Authors: Jeong-Hyun Ryou, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, Sho Hangai
Journal: Cancer Research (2022)

Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of myeloid cells that are highly suppressive to antitumor lymphocyte function and trafficking to the tumor. The accumulation of MDSCs in the tumor immune microenvironment (TIME) makes immunosuppressive TIME and progressive tumor. In fact, despite notable clinical outcomes in cancer immunotherapy, many patients are refractory or relapsed to immune checkpoint inhibitor therapy, wherein obstacles imposed by TIME contribute to a great extent. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME in mouse models. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME, which is Toll-like receptor-2 (TLR2) dependent. For human translation, we confirmed that human TCTP binds directly to human TLR2 extracellular domain and stimulates human PBMC to produce multiple cytokines. To explore therapeutic applicability, we generated anti-TCTP antibodies for TCTP inhibition. The antibodies successfully neutralized TCTP in molecular and cellular level. The antibodies also suppressed PMN-MDSC accumulation and tumor growth. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergistic effect on tumor growth inhibition. In conclusion, extracellular TCTP is an immunomodulator recruiting PMN-MDSCs to TIME. When TCTP is removed or neutralized, PMN-MDSC counts in TIME decreased. Anti-TCTP therapy may offer a new immunotherapy strategy. Citation Format: Jeong-Hyun Ryou, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, Sho Hangai. TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 242.
Abstract 2048: <i>In vitro</i> and <i>in vivo</i> characterization of non-oncolytic engineered arenavirus vectors for cancer immunotherapy
Authors: Josipa Raguz, Theresa Kleissner, Sandra Rosskopf, Mohamed Habbeddine, Katharina Lechner, Valentin Just, Donna Edwards, Igor Matushansky, Christoph Lampert, Klaus K. Orlinger, Henning Lauterbach
Journal: Cancer Research (2022)

Abstract Cytotoxic CD8+ T cells are paramount for effective cancer immunotherapy. We engineered two distantly related arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PICV), encoding the same non-oncogenic HPV16 E7E6 fusion protein to effectively mount and maintain tumor specific CD8+ T cell responses. The designated vectors, HB-201 (LCMV) and HB-202 (PICV), are currently in an ongoing Phase I/II open labelled clinical trial of HB-201 single vector therapy and HB-202/HB-201 alternating two-vector therapy in patients with treatment-refractory HPV16+ cancers (NCT04180215). To characterize the immunogenic properties of both vectors, we designed a comprehensive set of preclinical and translational experiments utilizing human PBMCs, artificial APCs and HPV16 E6 and E7 specific reporter T cells. This was done in conjunction with a preclinical model for HPV16 associated cancer (TC-1). HB-201 (LCMV) and HB-202 (PICV) surrogate vectors encoding GFP readily infected human monocytes, plasmacytoid dendritic, and conventional dendritic cells. In addition, HB-201 and HB-202 vectors successfully induced antigen presentation of E7 and E6 epitopes as evidenced by TCR reporter cells. Innate immune cell activation and cytokine responses to HB-202 were slightly lower compared to HB-201, findings which are consistent with different memory profiles of E7 specific CD8+ T cells in non-tumor bearing mice. In a therapeutic setting of the TC-1 tumor model, both vectors were comparably effective, showing major infiltration of CD8+ T cells into the tumor microenvironment, tumor growth delay and a significantly prolonged survival already after a single administration. In this data set we have confirmed the strong immunogenicity of the engineered arenavirus platform leading to efficient tumor control in a relevant mouse model for HPV16+ cancers, which further supports the clinical development of our novel arenavirus platform. Citation Format: Josipa Raguz, Theresa Kleissner, Sandra Rosskopf, Mohamed Habbeddine, Katharina Lechner, Valentin Just, Donna Edwards, Igor Matushansky, Christoph Lampert, Klaus K. Orlinger, Henning Lauterbach. In vitro and in vivo characterization of non-oncolytic engineered arenavirus vectors for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2048.
P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia
Authors: Kevin H. Lin, Justine C. Rutter, Abigail Xie, Shane T. Killarney, Camille Vaganay, Chaima Benaksas, Frank Ling, Gaetano Sodaro, Paul-Arthur Meslin, Christopher F. Bassil, Nina Fenouille, Jacob Hoj, Rachel Washart, Hazel X. Ang, Christian Cerda-Smith, Paul Chaintreuil, Arnaud Jacquel, Patrick Auberger, Antoine Forget, Raphael Itzykson, Min Lu, Jiaxing Lin, Mariaelena Pierobon, Zhecheng Sheng, Xinghai Li, Ashutosh Chilkoti, Kouros Owzar, David A. Rizzieri, Timothy S. Pardee, Lina Benajiba, Emanuel Petricoin, Alexandre Puissant, Kris C. Wood
Journal: Nature Cancer (2022)
Abstract 3833: The role of chemotherapy-induced fibrosis in the maintenance of tumor initiating cells
Authors: Omar Lujano-Olazaba, Mikella Robinson, Samuel F. Gilbert, Emily Kogan, Carrie D. House
Journal: Cancer Research (2022)

Abstract Around 80 percent of high-grade serous ovarian cancer patients will relapse with chemotherapy resistant disease. Despite extensive research and developments in immunotherapy, there are limited improvements in overall survival for these patients. Recent research has found that the tumor microenvironment (TME) plays a crucial role in tumor initiation, therapy resistance, and tumor relapse. The TME, which consists of immune cells, blood vessels, and an extracellular matrix (ECM) built primarily by fibroblasts, may enhance the survival and growth of tumor-initiating cells (TICs), chemoresistant stem-like cells thought to be responsible for tumor relapse. Cytotoxic chemotherapies have been shown to modify the TME and this modulation may favor the survival of TICs. For example, carboplatin can activate stromal cells such as fibroblasts to secrete an altered ECM profile, including increases in collagen 1a1 and fibronectin production, which can bind specific integrins upregulated in TICs. Using ex-vivo decellularized peritoneum tissues from mice exposed to chemotherapy or vehicle treatment, we observed a 2-fold increase in growth in peritoneums pre-exposed to chemotherapy relative to those pre-exposed to vehicle. We hypothesize that alterations in the ECM following chemotherapy treatment permit TIC adhesion and growth. To investigate this, mouse embryonic fibroblasts (3T3s) were exposed to chemotherapy during ECM production, decellularized, and reseeded with a panel of ovarian cancer cell lines. Our results suggest a significant increase in cell survival in matrices pre-exposed to chemotherapy compared to control matrices pre-exposed to vehicle. Using this model, we are examining the features of cells that preferentially survive on these matrices. In addition to drug resistance, we are using flow cytometry to assess TIC markers, such as CD117, and CD133, and qRT-PCR to measure stemness genes such as SOX2, OCT4, and NANOG. These studies highlight the need for further investigation into the systemic effects of chemotherapies on the TME and how these changes may be fostering cancer cell adhesion, growth, and survival. Understanding these mechanisms will allow us to develop therapies to achieve better clinical outcomes. Citation Format: Omar Lujano-Olazaba, Mikella Robinson, Samuel F. Gilbert, Emily Kogan, Carrie D. House. The role of chemotherapy-induced fibrosis in the maintenance of tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3833.
Ketamine exerts its sustained antidepressant effects via cell-type-specific regulation of Kcnq2
Authors: Juan Pablo Lopez, Malte D. Lücken, Elena Brivio, Stoyo Karamihalev, Aron Kos, Carlo De Donno, Asaf Benjamin, Huanqing Yang, Alec L.W. Dick, Rainer Stoffel, Cornelia Flachskamm, Andrea Ressle, Simone Roeh, Rosa-Eva Huettl, Andrea Parl, Carola Eggert, Bozidar Novak, Yu Yan, Karin Yeoh, Maria Holzapfel, Barbara Hauger, Daniela Harbich, Bianca Schmid, Rossella Di Giaimo, Christoph W. Turck, Mathias V. Schmidt, Jan M. Deussing, Matthias Eder, Julien Dine, Fabian J. Theis, Alon Chen
Journal: Neuron (2022)